The antiretroviral factor A3G does more than mutate HIV, report Casartelli and colleagues. It hastens the deployment of cytotoxic T cells.

A3G (short for APOBEC3G) is a restriction enzyme that inhibits HIV replication by introducing mutations into the viral genome. The team found that this editing strengthens the HIV-specific cytotoxic T lymphocyte (CTL) response. When HIV-infected cells expressed A3G, truncated viral peptides were loaded onto MHC class I machinery and were efficiently presented to HIV-specific CD8+ T cells. Wild-type HIV strains elicited a weaker response than strains missing their A3G-degrading weapon, the protein Vif. Although interferons in the innate arm of the immune system set off A3G, the authors show that the protein's enzymatic activity is critical for optimizing adaptive immunity.

To explain why imperfect viral peptides enhanced cytotoxic T cell activity, the authors invoked the controversial DRiP (defective ribosomal products) hypothesis, which predicts that most antigenic peptides originate from truncated proteins that degrade rapidly and enter into the MHC class I antigen–processing pathway. In fact, HIV made to artificially express severed Gag proteins, like those altered by A3G, enhanced CD8+ T cell activation.

The control A3G has over HIV may help account for why the disease does not affect people equally. It's possible that elite controllers—HIV-infected individuals who successfully suppress the virus—may have an A3G polymorphism to thank. However, the correlation between their polymorphisms and their CTL response has yet to be investigated.